1. Field of the Invention
The present invention relates to the use of aluminum salts in the treatment of bone disease.
2. Description of the Background
Bone is a dynamic tissue which constantly remodels itself throughout life. The properties of this tissue are a function of the particular organization of its extracellular components. The structure of bone tissue consists of a solid mineral phase in close association with an organic matrix consisting of 90-95% collagen, small amounts of proteoglycans and some non-collagenous proteins including proteins containing a-carboxyglutamic acid. The mineral phase is composed of hydroxyapetite, having the empirical formula Ca.sub.10 (PO.sub.4).sub.6 (OH).sub.2, of small crystal size and poor crystallinity, and so-called "amorphous" calcium phosphate, having a lower molar calcium/phosphorus ratio than that of hydroxyapetite.
The mineral phase of bone is deposited in intimate relation to the collagen fibrils and is found, for the most part, in specific locations within the collagen fibrils. The architectural organization of the mineral and matrix phases are uniquely suited to withstand mechanical stresses. In fact, the skeleton has extraordinary mechanical functions well-suited to the needs of mobile vertebrates. For example, the particular arrangement of compact and cancellous bone provides an excellent combination of bone strength and density for these needs. Additionally, bone provides a store of calcium, magnesium, phosphorus, sodium and other ions necessary for the support of a variety of homeostatic functions.
Bone is formed by cells of mesenchymal origin which synthesize and secrete the organic collagenous matrix. Mineralization of the matrix appears to commence soon after secretion, but is usually not completed until after several weeks. Osteoblasts synthesize and secrete the matrix, which is then mineralized. These cells once surrounded by the matrix become osteocytes, which remain connected to the blood supply through a series of canaliculi.
In the embryo and in the growing child, bone develops either by primary modeling and replacing of previously calcified cartilage, i.e., endochondral bone formation, or it is formed without a cartilage matrix, i.e., intramembranous bone formation. The young new bone has a relatively high ratio of cells to matrix and is characterized by coarse fiber bundles of collagen which are interlaced and randomly dispersed. In adults, the more mature bone is organized with fiber bundles regularly arranged in parallel or concentric sheets.
Growth of bone in width and in thickness is accomplished by the formation of bone at the periosteal surface and resorption at the endosteal surface with the rate of formation exceeding that of resorption. As noted above, however, bone remodeling, even in adults, is a continuous process occuring throughout life. In fact, kinetic studies using isotopes such as radioactive calcium (.sup.47 Ca) provide estimates that as much as 18% of the total skeletal calcium may be deposited and removed each year. Moreover, it appears that this constant bone remodeling is effected in a manner related to the continuous mechanical stresses to which the bone is subjected.
Bone formation is an orderly process in which inorganic materials such as calcium and phosphorus are desposited in a collagenous matrix. As the mineral phase is composed largely of calcium and phosphorus, the concentration of these ions in the blood plasma and extracellular fluid influences the rate of mineral phase formation. However, the concentration of these ions at the sites of mineralization is unknown and it is possible that osteoblasts and osteocytes may be involved in regulating the local concentration of these and other ions.
Nevertheless, there appears to be a lower limit for the concentration of calcium and phosphorus in the extracellular fluid below which the mineral phase will not be formed. Conversely, when these concentrations are excessive, the formation of mineral phases is observed in areas that are not normally mineralized.
During the resorption of bone, calcium and phosphorus ions from the solid phase are released into solution in the extracellular fluid, and subsequently, the organic matrix is also resorbed. Although the resorption mechanism is not entirely clear, it has been postulated that a decrease in pH, the presence of one or more chelating agents or the operation of a cellular pump mechanism to shift the equilibrium between solids and solution may be involved.
A number of diseases in man are characterized by diminished bone volume. Osteoporosis is the term used to describe the group of diseases of diverse etiology which are characterized by a reduction in the mass of bone per unit volume to a level below that required for adequate mechanical support. Histologically, osteoporosis is characterized by a decrease in the number and size of the trabeculae of cancellous bone with normal width of the osteoid seams.
Any combination of changes in the rates of formation and resorption which results in an excess of bone resorption relative to formation can cause a decrease in bone mass. In osteoporosis the bone mass is decreased, indicating that the rate of bone resorption must exceed that of bone formation.
Resorption and formation of bone are normally tightly coupled processes. However, the rate of remodeling is not uniform throughout the skeleton after epiphyseal closure. In fact, some of the bone surfaces are "inactive" and not involved at any given time either in formation or resorption. Resorption areas are covered by osteoclasts if active, whereas bone formation surfaces are characterized by the presence of osteoid seams and are covered by active osteoblasts. Thus, while the active surfaces may be randomly distributed, formation and resorption are coupled as so-called "remodeling units."
After the age of about 35 to 40 years, the human skeletal mass begins to decline in different parts of the skeleton. Evidence obtained from kinetic studies, using radioactive isotopes of calcium and phosphorus, and from quantitative microradiography, of both cortical and cancellous or trabecular bone indicates that in most subjects the resorption rate is higher than normal, whereas the bone formation rate is somewhat lower. Radioactive calcium kinetics indicate that as much as 400 to 500 mg of calcium may enter and leave the normal adult skeleton daily. At some critical point, if the difference between rates of formation and resorption is maintained, loss of bone substance may become so pronounced that the bone can no longer resist the mechanical forces to which it is subjected, and fracture occurs. Osteoporosis would then be presented as a clinical problem. Unfortunately, the cause of this age-associated decrease in bone mass and increase in bone resorption, which occurs particularly in older women after menopause, is not known. However, it has been estimated that, at present, approximately 50 million perimenopausal and postmenopausal women are afflicted with this condition.
Presently, all attempts to treat this disorder are prophylactic in nature. For example, medicinal agents commonly employed such as supplements of calcium, estrogens, vitamin D, and calcitonin are designed to inhibit bone resorption, and thereby merely retard the natural evolution of bone loss which occurs with aging. While such treatments are of some use, they suffer from two serious disadvantages. First, the success of these treatments depends, to a critical extent, upon the early identification of at-risk subjects before irreversibly damaging bone loss has occured. Secondly, even if such early identification is achieved, the success is limited in that all that is accomplished is a slowing of a seemingly inevitable and naturally occuring process. Thus, with the U.S. population living to an older age, we are, in essence, only succeeding in delaying the still inevitable onset of osteoporosis.
Although several drugs which are presently in investigational stages appear to have some capability of increasing bone volume, each has serious drawbacks which limit the utility thereof. For example, the application of fluoride ions in chronic high doses appears to increase new bone formation. However, these high doses tend to produce a form of hyperostosis with dense bones, exostoses, neurological complications due to bony overgrowth, and ligamentous calcification. Also, the administration of fluoride ions is often associated with the appearance of ulcers, arthritides and osteomalacia, wherein there is defective mineralization of the newly formed organic skeletal matrix. Furthermore, the use of fluoride in treating osteoporosis has not been found to produce uniformly satisfactory results, possibly due to variations in dosage, retention of absorbed ion and concurrent calcium intake.
Parathyroid hormone (PTH) has been observed to increase trabecular bone volume to some extent, however, only at the expense of cortical bone. In essence, administration of parathyroid hormone robs cortical bone in order to build trabecular bone. Cortical bone is characterized by having canals therethrough for blood passage. By contrast, trabecular bone is characterized by having islands of bone immersed in the marrow, and, therefore, has a large surface area. Inasmuch as metabolic changes in bone occur mainly on the bone surfaces, bones with high surface areas are the most susceptible to formation and resorption cycles.
While some bones, such as the more compact bones, are about 90% trabecular bone, other bones, such as the wrist bones are about 90% cortical bone. Hence, forming trabecular bone at the expense of cortical bone is a serious disadvantage when administering parathyroid hormone.
In some cases of severe bone fracture or destruction by disease, various artificial devices such as metal plates have also been used to effect internal bone fixation. Typically, a metal plate is placed on the bone to bridge the fracture and afford rigidity and strength during healing. Such plates are normally made from cobalt, titanium alloys or stainless steel. Unfortunately, the desired purpose of bone formation may be defeated by resorption of the bone when insufficient stress is placed on the bone. Moreover, most metals readily undergo fatigue fracture in physiological environments if the bone does not heal. While some advances have been made with polymeric plates, polymeric materials often result in the necrosis of nearby tissues due to residual monomer.
Clearly, in view of the above, there are no therapies currently available for inducing bone formation. While there are therapies and techniques for diminishing bone resorption, all of these methods suffer from severe drawbacks. Additionally, even the use of artificial mechanical supports, such as metal or polymeric plates, is greatly hampered by side effects or inherent limitations.
Accordingly, a need continues to exist for a method for stimulating the formation of new bone. Further, it would be very desirable if a method for stimulating new bone formation could be attained which uncouples the formation process from the resorption process which is normally coupled thereto.